Cycloaddition reactions oxazole-olefin

Since perfluoroalkyl-substituted olefins and alkynes possess low-lying frontier orbitals, [4 + 2] cycloaddition reactions to oxazoles and thiazoles without strongly electron-donating substituents are unfavorable. On the other hand, five-membered heteroaromatic compounds possessing an electron-rich diene substructure, like furans, thiophenes, and pyrroles, should be able to add perfluoroalkyl-substituted olefins as well as alkynes in a normal Diels-Alder process. A reaction sequence consisting of a Diels-Alder reaction with perfluoroalkyl-substituted alkynes as dienophile, and a subsequent retro-Diels-Alder process of the cycloadduct initially formed, represents a preparatively valuable method for regioselective introduction of perfluoroalkyl groups into five-membered heteroaromatic systems. 

Since the early demonstrations of the participation of substituted 1,2,4,5-tetrazines and oxazoles in Diels-Alder reactions with olefinic and acetylenic dienophiles, the potential utilization of the [4 + 2] cycloaddition reactions of heteroaromatic systems possessing a suitable azadiene arrangement has been the focus of extensive investigations. In general, the heteroaromatic systems which possess an electron-deficient azadiene... 

Although the regiochemistry of oxazole-olefin cycloadditions has not been extensively studied, some generalizations can be made. The major product is the 4-substituted pyridine in those instances when the alkene dienophile bears an electron-withdrawing substituent. This regioselectivity is exemplified by the Diels-Alder reaction used in a synthesis of the natural product ellipticine by Kozikowski and Hasan," starting from the reaction of oxazole 21 with acrylonitrile to give 4-cyanopyridine 22 (Fig. 3.6). 

The azaphenanthrene alkaloid eupolauramine appeared to be an ideal target for exploring the applicability of an intramolecular Kondrat eva pyridine synthesis in the construction of natural products. Despite the fact that 2-phenyloxazoles are unreactive in intermolecular cycloadditions, the Diels-Alder reaction of oxazole-olefin 97 was expected to provide the tricyclic framework of eupolauramine... 

The regiochemistry of oxazole-alkyne cycloadditions is ill-defined except for the reactions of electron-rich 5-alkoxyoxazoles with electron-deficient alkynes. In these cases, as for the analogous oxazole-olefin cycloadditions, the major product results... 

Similar to oxazole-olefin cycloadditions, the rate of Diels-Alder reactions of oxazoles with acetylenes depends on the electron-donating ability of the oxazole substituents. Rates decrease with decreasing electron-donating capacity of the substituents, in the order OR > NR1R2 > alkyl > 4-phenyl > COCH3 > CO2CH3 2-,5-phenyl. 5-Alkoxyoxazoles are approximately equivalent in reactivity to an all-carbon diene. 

Several additional examples of oxazole Diels-Alder reactions applied to the synthesis of natural products have appeared. Using the same synthetic strategy that resulted in the total synthesis of normalindine, " Ohba and co-workers adapted the oxazole-olefin Diels-Alder cycloaddition for the synthesis of the mono-terpene alkaloids plectrodorine and oxerine. The synthesis of (-)-plectrodorine began with the requisite Diels-Alder precursor 262a, prepared from (5)-(-)-malic acid (Fig. 3.78). The intramolecular Diels-Alder reaction of this 2-alkyloxazole... 

Thermal IMDA reaction of acetylene-tethered oxazoles was a key step in the synthesis of tropoloisoquinoline alkaloids <01JA3242>, while the analogous conversion of suitable oxazole-olefins to cyclopenta[c]pyridines was promoted by catalytic amounts of Cu(II) triflate <01H(55)823>. DA cycloadditions of methyleneoxazolones 150 with dienes afforded spirooxazolones 151 which were legio- and diastereoselectively converted to carbocyclic... 

Five-Component Synthesis of Hexasubstituted Benzene Cycloaddition of oxazole with olefin afforded functionalized pyridine after fragmentation of the oxa-bridged cycloadduct (Eq. (1), Scheme 15.19). Logically, if an alkyne were used as a partner of oxazole, the cycloaddition would give an oxa-bridged cyclohexadiene that could undergo the retro-DA reaction to provide a substituted furan (Eq. (2), Scheme 15.19). 

The use of the CFs-substituted oxazole as an aza-diene for a Diels-Alder reaction was briefly examined. Thus, prolonged heating of the mixture of 5-ethoxy-4-trifluoromethyloxazole and an excess of acrylic acid afforded the CFs-substituted pyridine derivative in reasonable yield [61], However, cycloaddition with other olefins, such as ethyl acrylate, N-phenylmaleimide, 2,5-dihydrofuran, maleic anhydride, and 2-buten-4-olide did not take place to any appreciable extent presumably because of the deactivation of the oxazole ring by a strongly electron-withdrawing CF3 group. 

Gollnick and Koegler also conducted detailed mechanistic studies of the [4 + 2] cycloaddition of O2 with oxazoles. The authors characterized the first examples of disubstituted oxazole 2,5-endoperoxides 702 (Scheme 1.195). These endoperoxides were particularly interesting since the presence of an olefinic proton permitted structure assignment based on low-temperature (—50 C) H and NMR data. The authors were able to mle out 694 and 703-705 as possible intermediates in this reaction, and they unequivocally identified the intermediates as the oxazole 2,5-endoperoxides 702. 

That these reactions proceed via the intermediacy of a Diels-Alder cycloaddition adduct has been affirmed by the isolation of a variety of the 1 1 Diels-Alder adducts.For example, the reaction of 5-ethoxy-4-methyloxazole 8 with cis-2,5-dimethoxy-2,5-dihydrofuran 9 provided the isolable endo and exo adducts 10 and 11 respectively, in a 2 1 ratio (Fig. 3.4). Similarly, 5-ethoxy-4-oxazoleacetic acid ethyl ester 12 reacted with maleic anhydride to provide the stable endo and exo adducts 13 and 14, in which the olefin has moved into conjugation with the ester moiety. In this case, compound 13 was the sole product when the reaction proceeded at 10°C, but only the exro-adduct 14 was isolated if the cycloaddition was conducted at 80°C. Heating at 50°C for 3h converted 13 into 14. The 2-carboethoxy analog of oxazole 12 behaved similarly. ... 

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